Cancer Prevention-Interception Against MGUS Progression

项目摘要 意义不明的单克隆丙种球蛋白病（MGUS）是一种癌前病变， 血液中异常免疫球蛋白（IG）蛋白（称为M蛋白）水平中度升高。 MGUS患者的癌症风险是对照人群的6.5倍。MGUS可能会发展到 多发性骨髓瘤（MM）、Waldenström巨球蛋白血症（WM）、非霍奇金淋巴瘤（NHL）、慢性 淋巴细胞白血病（CLL）、淀粉样轻链（AL）淀粉样变性或浆细胞瘤。MM，WM，大部分 NHL和AL淀粉样变性是不可治愈的疾病。CLL和浆细胞瘤很少治愈。意义 的MGUS呼吁癌症预防拦截U 54专门中心致力于这种癌前病变 MGUS影响约1%的人群，MGUS进展为癌症或其他相关血液病 疾病持续以每年约1%的速度，约90%的癌症/疾病从MGUS进展， 无法治愈所有MGUS患者都是癌症预防和拦截的潜在候选人。我们 假设促癌分子和骨髓微环境促进MGUS 进展是精确癌症预防和拦截的合适靶点。我们建议设立 癌症预防-阻止MGUS进展为癌症（CAP-MGUS）中心作为一个灵活的， 致力于预防MGUS进展的有效网络基础设施。本中心将承担 合作研究，重点是免疫和化学靶向剂，防止或拦截 MGUS或郁积性疾病患者的致癌过程。我们提出了三个目标，以实现 CAP-MGUS中心的首要目标。在目标1中，我们将对肿瘤中的几个癌靶点进行功能验证 启动和进展为浸润性癌症，并确定其是否适合有针对性的干预策略。 在目标2中，我们将通过体外实验发现创新的免疫和化学预防和拦截剂， 和体内功效评价。在目标3中，我们将通过确定癌症的新靶点来开发新项目- 对MGUS进展的预防性或阻断性干预。总的来说，我们希望 用于进一步开发或早期临床试验的化学预防剂和免疫预防剂。

Project Summary Monoclonal gammopathy of undetermined significance (MGUS) is a precancerous condition in which a person has moderately elevated levels of an abnormal immunoglobulin (Ig) protein (called M protein) in the blood. MGUS patients have a cancer risk ~6.5 times as high as the control population. MGUS may progress to multiple myeloma (MM), Waldenström macroglobulinemia (WM), non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), amyloid light-chain (AL) amyloidosis, or plasmacytoma. MM, WM, a large portion of NHL, and AL amyloidosis are incurable diseases. CLL and plasmacytoma are rarely cured. The significance of MGUS calls for a cancer prevention-interception U54 Specialized Center dedicated to this precancerous condition  MGUS affects ~1% of the population, MGUS progresses to cancer or other associated blood disorders persistently at a rate of ~1% per year, and ~90% cancer/disorder that progressed from MGUS are incurable. All patients with MGUS are potential candidates for cancer prevention and interception. We hypothesize that cancer-driving molecules and the bone marrow microenvironment promoting MGUS progression are suitable targets for precision cancer prevention and interception. We propose to establish the Cancer Prevention-Interception against MGUS Progression to Cancer (CAP-MGUS) Center as an agile and effective network infrastructure dedicated to preventing MGUS progression. This Center will undertake collaborative research focusing on immunologically and chemically targeted agents that prevent or intercept the oncogenic process in patients with MGUS or smoldering diseases. We propose three aims to achieve the CAP-MGUS Center’s overarching goal. In Aim 1, we will functionally validate several oncotargets in tumor initiation and progression to invasive cancer and ascertain their suitability for targeted intervention strategies. In Aim 2, we will discover innovative immuno- and chemo-prevention and interception agents through in vitro and in vivo efficacy evaluation. In Aim 3, we will develop new projects by identifying novel targets for cancer- preventive or interceptive interventions against MGUS progression. Collectively, we expect to obtain chemoprevention and immunoprevention agents for further development or earlier phase clinical trials.